CD8+ T cells are key players in the immune response to intracellular infections such as HIV. However, during chronic infection HIV-specific CD8+ T cells become tolerant in that they do not proliferate or kill infected targets as efficiently as virus-specific T cells from other non-persistent viral infections (e.g. influenza). We have shown that HIV-specific T cells restricted by HLA alleles associated with non-progression (HLA-B27/-B57) are resistant to this type of peripheral tolerance, which may explain why rare HIV-infected individuals are protected from progression to AIDS. The mechanism(s) leading to HIV-specific CD8+ T cell tolerance are not known but understanding them is vital to making therapeutic intervention possible. Regulatory T cells (Tregs) are one of the best-described mediators of peripheral tolerance. Our preliminary data show that HIV-specific T cells restricted by HLA-B27/-B57 are resistant to Treg-mediated suppression of proliferative capacity whereas HIV-specific T cells restricted by other HLA alleles are susceptible to Treg-mediated suppression. In this proposal we aim to decipher how Tregs are causing differential suppression of HIV-specific T cells. In Aim 1, we will determine if HIV-specific CD8+ T cells that are resistant to Treg suppression are a common phenomenon in individuals who can control HIV-1. In Aim 2, we will determine which mechanism(s) are utilized by Tregs to suppress HIV-specific T cell responses during chronic infection and how T cells restricted by HLA-B27/B57 are able to escape from this suppression. This study could define why certain HLA alleles are associated with non- progression in HIV-infected individuals. In addition, if we define how specific T cells escape from Treg- mediated suppression this work could have far-reaching implications for therapeutic intervention in other chronic viral infections, cancer and autoimmune disease. PUBLIC HEALTH RELEVANCE: This proposal aims to determine (1) whether HIV-specific T cells that escape Treg-mediated suppression are a common phenomenon in individuals who control HIV-1 infection;(2) the mechanisms utilized by Tregs to suppress HIV-specific T cell function;and (3) how HIV-specific HLA-B27/57-restricted T cells are able to escape Treg-mediated suppression.